2-amino-3-(p-chlorophenylimino)-3, 5-dihydro-5-(p-chlorophenyl)-phenazine and salts thereof



the raw products obtained United States Patent Vincent ChristopherBarry, briel Belton, Terenure, 'Conalty, Dublin, and

Rathgar, Dublin, James Ga- Dnblin, Michael Laurence Dermot Twomey,Terenure, Dublin, Ireland, assignors, by mesne assignments, to GeigyChemical Corporation, New York, N. Y., a cor poration of Delaware NoDrawing. Application November 4, 1955 Serial No. 545,101

Claims priority, application Switzerland November 8, 1954 2 Claims. (Cl.260-267) The present invention is concerned with phenazine derivativeswhich have chemotherapeutically valuable properties.

As M. Schtipf, B. 23, 1843 first observed, on oxidisingN-phenyl-o-phenylene diamine with ferric chloride, a dyestuff resultswhich was identified by O. Fischer and O. Heiler, B. 26, 381 as2-anilino-3.5-dihydro-3-imino-5- phenyl phenazine (anilino-aposafranineor anilido phenyl induline) of the formula:

Then Kehrmann considered the isomeric constitution:

see B. 28, 350 (1895) but he was convinced of the accuracy of theFischer formulation in particular by the degradation to the2-anilinoaposafranine, by O. Fischer and co-workers, B. 26, 382, B. 29,364, B. 29, 1604. The compound of the formula suggested by Kehrmann andsubstitution products thereof could not be isolated from on theoxidation with ferric chloride.

Lately, 2-anilino-3.5-dihydro-3-imino-5-phenyl phenazine as well asanalogues and substitution products thereof have become of interestbecause of their activity against the tubercle bacillus, see Nature 162,622-23 (1948).

Most surprisingly it has now been found that the 2,875,204 Patented Feb.24',

2. isomeric compound in which substituted instead of the 2+; correspondsto the formula:

' mineral acid salts, of the the S-imino group is aryl amino group andwhich N (I NH N (III) can be produced in a simple way by oxidisingmineral acid salts of the compound of the formula:

(Iv) in an aqueous solution with p-benzoquinone. By the use ofbenzoquinone instead of ferric chloride as oxidismg agent, a new groupof compounds is attained which 25 is of chemotherapeutical value, inparticular for the treatment of tuberculosis and leprosy. Thatbenzoquinone is at all suitable for the oxidation of theN-aryl-o-phenylene diamines, i. e. compounds with a primary basic aminogroup, was just as unlikely to have been foreseen as the fact that theisomer with p-chlorophenyl-substituted 3- imino group (Formula III)which up to the present have not yet been isolated, would result fromthis oxidation. Compared with the corresponding isomers analogous toFormula I which are aryl substituted at the amino nitrogen atom, theyhave been found to have a stronger tuberculostatic action inpharmacological trials on animals. This is also the case when comparedwith pamino salicyclic acid and the most active thiosemicarbazones. Inparticular it should be stressed that their inhibitive action ontubercle strains which have become resistant toisonicotinic acidhydrazide is stronger than their inhibitive action on tubercle strainswhich have the normal sensitivity to isonicotinic acid hydrazide. Forthis reason they may be used in combined therapy, e. g. withisonicotinic acid hydrazide or other tuberculostatically activecompounds.

It is of advantage to perform the oxidation at a moderately hightemperature, e. g. -70, while using 1 to 2 mols of benzoquinone per onemol of N-p-chlorophenyl- 0 o-phenylene diamine. The anhydro base of theFormula III can be liberated from its mineral acid salts e. g. by meansof alcoholic alkalies. Isomeric compounds analogous to Formula I resultas side products, most of which have better solubility in benzene and,in the form of their hydrochlorides are more easily soluble for examplein alcohol. It is thus generally easy to separate the de sired base ofthe Formula III or the hydrochlorides thereof from the solutions of thecorresponding mixtures, to a great extent by allowing them tocrystallise.

To obtain chemotherapeutical active substances however, it is notnecessary to attain the base of the Formula IH free from their isomersas, in some circumstances, the

latter can be active themselves and the two isomers 'can probably have asynergistic effect.

The following example illustrates the production of the new compounds.Parts are given as parts by weight and the temperatures are in degreesCentigrade.

Example 12.2 parts of N-(4-chloro phenyl)-o-phenylene diarninehydrochloride dissolved in 300 parts of hot water were added dropwisewhile stirring to a solution of 9 parts of benzoquinone in 200 parts ofhot water (60). The

dark precipitate which formed was boiled with alcoholic irnino)-3.S-dihydro-S-(p-chlorophenyl) -phenazine was obtained in'the form ofdark red shining needles which eontained one mol of benzene, M. P.233-236.

What we claim is:

' 1. A member selected from the group consisting of2-amino-3-(p-chlorophenylimino) 3,5 dihydro 5 (pchlorophenyl)-phenazineand the mineral acid salts thereof.

2. 2amino-3-(p-chlorophenylimino) 3,5 dihydro-S- (p-chlorophenyl)-phenazine.

References Cited in the file of this patent

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF2-AMINO-3(P-CHLOROPHENYLIMIMINO) - 3,5 - DIHYDRO - 5 -(PCHLOROPHENYL)-PHENAZINE AND THE MINERAL ACID SALTS THEREOF.